The overall goal of the previous cycle was to improve our understanding of functional energetics of cortical neurons in relation to their metabolic and hemodynamic demands in order to bridge the gap between the macroscopic BOLD signal and the underlying microscopic electrical activity of neural cells. We integrated high- field fMRI with 1H[13C]MRS and extracellular electrical recordings to provide high spatial and temporal measurements from different cortical layers. We effectively applied these tools in healthy rat brain under different arousal states and under clinical conditions such as absence or generalized seizures. Both tactile and non-tactile sensory systems were studied with variations of stimulus features to map the cortical surface. The multimodal results from different arousal states were then used to model oxidative neuroenergetic changes from transient to steady-state BOLD signal. Thus our ability to extract transient oxidative cerebral energetics (CMRO2) from dynamic coupling between neural (LFP, MUA) and vascular (CBF, CBV) signals has improved. We expanded our understanding about the relationship between BOLD activation patterns and baseline activity (or arousal level), where high frequency (or 3-band) baseline activity was correlated with spreading of cortical activity. Since recent studies reveal rich reciprocal interplay between cortical and subcortical networks, using cortical fMRI data alone to interpret function may be insufficient. The thalamus and the superior colliculus are vital for integration of different senses leading to activation of dispersed cortical regions. Multisensory integration, evident behaviorally and neurophysiologically, refers to crossmodal influences in the form of response enhancement or suppression. Furthermore level of cortical 3-band activity necessarily alters subcortical processing, because of the cortico-thalamic and cortico-colliculor projections. Thus the goal of this project is to study subcortical and cortical interactions in regards to crossmodal sensory integration based on the hypothesis that the BOLD signal and the neural response established in cortex are dependent on activities of subcortical areas given the hierarchy of sensory signal transfer. Research on multisensory integration has focused either on electrophysiology studies of individual neurons in animals or human fMRI studies investigating diffuse cortical areas involving millions of neurons. To bridge the gap in knowledge about crossmodal sensory mixing, an essential component of sensory perception, we will combine technology developments in high-field fMRI/MRS (multi-array RF coils with parallel imaging, dynamic and passive shimming, metabolic flux mapping) and electrophysiology (multi-electrode extracellular arrays) to characterize the BOLD responses of thalamus and superior colliculus, evaluate the neurometabolic and neurovascular couplings for BOLD calibration in cortical and subcortical regions, and assess the impact of the baseline state on multisensory BOLD activation patterns. Results from the proposed experiments will provide new insights into active interactions between cortical and subcortical areas and provide a mechanistic basis to interpret multisensory integration in human fMRI experiments and possibly even open new approaches to study sensory processes and their disorders in humans (e.g., aging, autism, dyslexia). PUBLIC HEALTH RELEVANCE: The energetic basis of neural activity provides solid basis for non-invasive neuroimaging with fMRI. The goal of the proposal is to study subcortical mechanisms underlying cortical activations for unisensory and multisensory stimuli. Results obtained from these studies will serve as a system to study questions raised in human fMRI studies and test concepts of crossmodal sensory mixing, which involve cortical and subcortical circuits and are known to be affected in various human sensory disorders (e.g., aging, autism, dyslexia).